Efficacy and Safety of Belimumab in Subjects With Primary Sjögren's Syndrome

Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by an increase in BAFF (BLyS) levels and a resulting B cell hyperactivity. B cells are involved in the pathogenesis of SS in both systemic and glandular features, and B cell downregulation may lead to a decrease of disease activity. Moreover, pathogenesis of SS is closed to that of Systemic lupus erythematosus, where Belimumab has been proven to be effective.

This phase II open-label study has 2 mains objectives:

• To evaluate the proof of concept of efficacy of belimumab in subjects with SS
• To evaluate the safety and tolerability of belimumab in subjects with SS Belimumab will be administered (10mg/kg on D0 D14 D28 and every 28 days for 24 weeks, with extension to 48 weeks if responders) to all patients

Inclusion criteria

• Have a diagnosis of primary SS according to the updated American European Consensus Group Criteria. In addition, patients must be always positive for anti-SSA or anti-SSB antibodies
• Have the presence, at screening, of Systemic involvement (polysynovitis, skin, renal, lung, CNS involvement, peripheral neuropathy, vasculitis, autoimmune cytopenia, defined in Annex 1) or persistent (up to 2 months) parotid, submandibular or lachrymal gland swelling of more than 2 cm OR

Objective sicca (positive oral and/or ocular tests reported in the American European Consensus Group Criteria) with at least one among the following biological features of serum B lymphocyte activation :

increased IgG levels increased free light chain levels of immunoglobulins (according to central laboratory ranges) increased serum beta2-microglobulin levels decreased C4 levels (C4 levels inferior to central laboratory ranges) monoclonal gammapathy cryoglobulinemia OR

• SS of more recent onset, i.e., less than 5 years of duration of symptoms, associated with:

• oral or ocular dryness
• fatigue
• musculoskeletal pain (i.e, 3 criteria for response as reported at page (ix-x), characterized by VAS score more than 50/100 in all the 3 fields.

Exclusion criteria

• Any BLyS-targeted (BLyS-receptor fusion protein [BR3], TACI Fc, or belimumab) at any time.
• Any of the following within 364 days of Day 0:

• B-cell targeted therapy (eg, rituximab, other anti-CD20 agents, anti-CD22 [epratuzumab], anti-CD52 [alemtuzumab]
• A biologic investigational agent other than B cell targeted therapy (eg, abetimus sodium, anti CD40L antibody [BG9588/ IDEC 131]).

4- Intravenous or oral cyclophosphamide within 180 days of Day 0.

5- Any of the following within 90 days of Day 0:

• Anti-TNF therapy
• Interleukin-1 receptor antagonist
• Abatacept
• Interleukin-6 receptor antagonist
• Intravenous immunoglobulin
• Prednisone > 100 mg/day
• Plasmapheresis.

9- Very severe SS disease.

10- Major organ or hematopoietic stem cell/marrow transplant.

11- Unstable or uncontrolled acute or chronic diseases not due to SS

13- History of malignant neoplasm within the last 5 years, except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix.

14- Required management of acute or chronic infections, as follows:

• Currently on any suppressive therapy for a chronic infection
• Hospitalization for treatment of infection within 60 days of Day 0.
• Use of parenteral (IV or IM) antibiotics

16- Historically or at screening positive test for HIV antibody, hepatitis C virus antibodies, or, hepatitis B surface antigen (HbsAg) (with or without positive serum HBV DNA), or antiHBcAg positivity (without anti-HbsAg positivity).

17- Grade 3 or greater laboratory abnormality based on the protocol toxicity scale except for the following that are allowed:

• Stable Grade 3 prothrombin time (PT) secondary to warfarin treatment.
• Stable Grade 3/4 proteinuria (≤ 6 g/24 hour equivalent by spot urine protein to creatinine ratio allowed). (mentioned earlier in Exclusion #8)
• Stable Grade 3 neutropenia or stable Grade 3 white blood cell count.